APPENDIX. Studies of Prostate-Specific Antigen for Prostate Cancer Screening and Early Detection

Transcription

1 APPENDIX D Studies of Prostate-Specific Antigen for Prostate Cancer Screening and Early Detection

2 APPENDIX D: STUDIES OF PROSTATE SPECIFIC ANTIGEN FOR PROSTATE CANCER SCREENING AND EARLY DETECTION: RESEARCH DESIGN AND FINDINGS Babaian 1992 ACS- NPCDP c Babaian 1991 Brawer et al., 1992 Catalona 1991 Catalona 1993 Chadwick et al., ,3,6,7,8 10 sites in U.S./Canada, (63) hospital/ clinic-based public 1,2,3,4,6,7,8 Cancer (most symptomatic) referral and selection biases 2,3,6,7,8 U.S. Urology >50 Clinic (67) 2,3,6,7,8 U.S. Urology Clinic (63 median) 2,3,6,7,8 U.S. Urology Clinic (63) 2425 over 3.5 years ( in 2,227) 362 (75 MD referral recorded) (not ) 90/362 (25%) /1,249 (15%) 1653 < 4 ng/ml 137/1653 (8.3%) 10,251 (but 622 protocol violations ) 9,629 screen 9,333 serial screen (up to 37 month followup) 3,4,6,7,8 British eligible populationbased gener screened al practice recruitment 437 got 407 got DRE 902/9629 (9.4%) 873/9333 (9.4%) serial 63/472 (13%) DRE and/or TRUS (11 additional biopsies for abn, most > 10 ng/ml) blinding not specified DRE and/or TRUS, or > 20 No blinding If > 4, then DRE/TRUS with systematic biopsy adjunct blinding not specified If > 4 on or 6 month re-test, then DRE and TRUS, biopsy if either abn blinding not specified If > 4 twice ly, or on any 6 month serial check then DRE an TRUS. If either abn, biopsy. No systematic biopsy If > 4 and/or DRE abnormal, TRUS recommended. If TRUS abn, biopsy recommend No. with No. (5) 520/2425 (21%) year year year /362 (33%) 109/362 (30%) 187/1249 (15%) 105/1249 (8.4%) 137/1653 (8.3%) 112/1653 (6.8%) 902/9629 (9.4%) 860/9629 (8.9%) 873/9333 (9.4%) 465/9333(5%) serial 75/472 (16%) 12 of 75 for abn DRE alone 29/472 (6%) 88/2,425 (3.6%) no data on grade/volume 37/362 (10%) 27/75 (36%) MD referred; 10/287 (3%) self referred 32/1249 (2.6%) no data on grade/ volume 37/1653 (2.2%) d no data on grade/volume 296/9629 (3.1%) 195/9333 (2.0%) serial 491/9629 (5.1%) total 7/472 (1.5%) (mean 17) size/volume 59/137 (43%) 23/37 (62%) 30/90 (33%) 30/32 (94%) 9/32 (28%) 4 of the 9 capsule penetration without perforation 16 surgical staging 36/37 (97%) 12/37 (32%) 33 surgical staging 277/296 (94%) 170/175 (97%) serial, but missing data 153/262 (58%) initiate, but 27 did not get surg stage 92/129 (71%) serial, but missing data in 46 7/7 (100%) 5/7 (71%) 5 surgical staging 32/105 (30%) 37/112 (33%) if /85 (22%) if > 10 18/27 (67%) 296/860 (34%) overall 174/652 (27%) /208 (59%) > 10, RP - 15 PL - 1 RT - 10 No TX - 6 (at least 19 had RP) Of total 491: RP RT - 68 HT - 27 No TX - 16 Pending - 32 (11%) 7/63 RP - 5 No TX Costs and Effectiveness of Prostate Cancer Screening in Elderly Men

3 Cooner 1990 Drago et 1,2,3,4,6,7,8 U.S. Group Urology Practice referral bias [selected population many symptomatic with prostatism of varyinge gree] al., 1992 e Guinan 1987 Actual prevalence Gustafsson ,2,3,5,6,7,8 U.S. Academic Inpatient Urology Service Comparative study of 5 studies, including TRUS,. All symptomatic selection bias. generalizable to officebased population. 6,8 Swedish Random selection populationbased (64) 1, asymptomatic No clear description of recruitment process. Annual followup over 4.5 years eligible (census database) 1,782 number of with urologic symptoms or evidence of BPH. 602/1,807 (33%) 4-10 ng/ml 366/1,807 (20%) > 10 ng/ml 236/1,807 (13%) 989/1,940 (51%) specified Mean plus 1 S.D. Hybritech 102/280 got (36%) 306/1782 (17%) TRUS (hypoechoic) No systematic biopsy. DRE, performed but not basis for biopsy No blinding. DRE and/or TRUS systematic biopsy not used 27 of on basis Abn but level not specified. Unknown for entire group: only 46/102 (45%) pos All 280 DRE, TRUS or > 10 ng/ml (systematic biopsy if >10). Patients received all 3 tests Abn DRE (nodule, induration, asymmetry) TRUS (hypo or asymmetry). No. with No. (5) 835/1,807 (46%) all 416/1940 (21%) Initial, 320 2nd, 80 3rd, 16 78/280 (28%) of tested 42/102 (41%) 371/1782 (21%) Average 3 fine needle aspirates/ patient and 2-4 core biopsy/ patient. 263/1,807 (14.5%) < 3.0 cc vol 172/263 (65%) > 3.0 cc vol 91/263 (35%) 79/1940 (4.1%) cumulative yield grade/tumor [57/79 (72%) of PC had >4] 65/1782 (3.6%) If age /481 (1.5%) age /585 (4.4%) age /716 (4.5%) alone 52/1782 (2.9%) 136/242 (56%) of data available 64/79 (81%) 40/65 (62%) (2.2% of 1782) T2A or less - 22 T2B /65 in peripheral zone 43/263 (16%) 60 surgically staged 31/46 (67%) sensitivity = 31/42 (74%) specificity = 45/60 (75%) 263/835 (32%) 57/137 (42%) of the 989 with > 4 not. RP /306 (17%) ,2,3 Mean specified. specified. Appendix D Studies of Prostate-Specific Antigen for Prostate Cancer Screening and Early Detection 83

4 Labrie et al., 1992 Mettlin et al., ACS- NPCDP, 6,8 Canadian 1991 f Mettlin ACS- NPCDP, 1993 g University Center Random selection, populationbased from electoral roles 2,3,6,7,8 10 sites in U.S./ Canada Hospital/Clinic (63) 2,3,6,7,8 10 sites in on U.S./Canada entry Hospital/ (63) Clinic (number ly not ) 2,425 over 3.5 years ( in 2,227) Report on screen 2,999 Annual evaluation up to 5 years Reporting on 1972 men with 2 sequential exams with complete data for primary variables. 124/1,002 (12.4%) >3 ng/ml 191/1,002 (19%) 312/2,227 (14%) > 4 nl/ml 271/1972 (21%) exam 248/1899 (22%) follow-up exam DRE and/or TRUS ( test for all but not biopsy for alone) If abnormal DRE but TRUS neg. six random biopsies DRE and/or TRUS (unknown number biopsy recommended for > 10 ng/ml) Blinding of tests not specified 71/271 (26%) with >4 49/248 (20%) with >4 on follow-up No. with No. (5) Provided. 396/2425 (16.3%) 330/2425 (13.6%) 70/312 (22%) with > 4 were 326/1972 (16.5%) Initial exam 216/1899 (11.4%) follow-up exam 285/1972 (14.5%) Initial 196/1899 (10%) 57/1,002 (5.7%) For > 4, 41/1,002 (4.1%) For > 3, 46/1,002 (4.6%) volume or grade 57/2,425 (2.4%) 5 of 57 on basis of > 10 ng/ml alone 73/1972 (3.7%) Initial exam 33/1899 (1.7%) exam 46/51 (90%) 6 others missing stage data 79/85 (93%) No data for 21 56/61 (92%) Initial 23/24 (96%) For > 4, 41/124 (33%) For > 3, 46/191 (24%) 21/31 (68%) 3 missing surgical stage data, 23 not staged < 1.0 cm - 10 > 1.0 cm - 40 No size data - 7 No volume data Grade: Gleason 4-6: 43 Gleason 7-8: 9 No data: 5 67/88 (76%) Gleason grade were grade /312 (11%) (5 of the 34 cancers had >10) 242/312 (78%) patient with > 4 were not. 49/271 (18%) Initial Exam 22/248 (9%) Exam Explicit number cancer with > 4 in and follow-up groups not overall 71/106 (67%) cancers had >4. RP - 34 RT - 10 HT - 3 Orchiectomy - 1 No TX - 4 RP - 59 RT - 17 No TX - 6 HT - 2 Orchiectomy - 3\ No data Costs and Effectiveness of Prostate Cancer Screening in Elderly Men

5 Moon 1991 Muschenheim 1991 Perrin Powell 2,3,4,5,6,7,8 University/ Veterans Administration Urology Clinic General public 2,3,4,5,6,7,8 General public (Prostate Cancer Awareness Week) French Recruited within clinic men attending for routine of 4-year checkup 1,2,3,4,6,7,8 Single British Referral population All men had prostatism symptoms prospective accrual, to prescreen most later got TURP not (68) referred /414 (2.4%) /190 (2%) /224 (4.5%) 59/565 (10.4%) 6 biopsies/ patient 38/863 (4.4%) > 10 ng/ml (Hybritech) 37/211 (17.5%) Implied that all received both and DRE with TRUS if either positive (not specified) Abn DRE (not specified) and/or elevated. No independent blinding specified If DRE Abn. for those with > 4 > 10 DRE not uniformly performed (not available for 23%) No TRUS used No. with No. (5) 11/414 (2.7%) 118/565 (21%) 54/565 (9.6%) 34/59 (58%) Abn. 37/211 (17.5%) 36/37 (97%) 5/414 (1.2%) If 40-49: 0/190 (0%) If 50-59: 5/224 (2.2%) white 2/153 (1.3%) black 3/71 (4.2%) 20/565 (3.5%) 5/20 grade poorly diff 4/5 (80%) Little detail 17/20 (85%) although insufficient detail 2/5 (40%) However, no uniform whole mount histologic technique 2 organ-confined may have been understaged grade/volume in sufficient detail. All 12 surgically staged had no lymph node disease. 9/12 (75%) presumed. (0.3%) 3/863 5/10 (50%) RP /59 (25%) For DRE alone: 16/83 (19%) RP - 12 RT - 4 Free screening Orchiectomy - 3 No TX /37 (46%) 1991 h ,2,3,4,6,7, (8%) 17/211 3/38 (8%). 8/17 (47%) Appendix D Studies of Prostate-Specific Antigen for Prostate Cancer Screening and Early Detection 85

6 Richie et al., 1993 i 2,3,6,7,8 6 University sites (63) 6630 [White - 6, /6630 Black (14.8j%) (3%) Other ABN (5.1%)] stratified by age: Symptoms of 50-59: BPH: 150/2381 (6%) Yes - 3, : (53%) No - 3,130 (47%) 487/2959 (17%) 311/1161 (27%) 80+: 35/129 (27%) DRE (asymmetry, induration or nodule) and/or elevated. If either abnormal, TRUS performed with guided biopsy if abnormal and systemic quadrant biopsies for all with elevated even if TRUS or DRE normal No. with No. (5) 1710/6630 (26%) 1167/6630 (17.6%) of meeting by age: 50-59: 364/2381 (15%) 60-69: 828/2959 (28%) 463/1161 (40%) 80+: 55/129 (43%) 264/6630 (4%) By age: 50-59: 48/2381 (2%) 6-69: 123/2959 (4.2%) 84/1161 (7.2%) 80+: 9/129 (7%) stratified by presence of symptoms 261/264 (99%) 114/160 (71%) of those received surgical staging 101 of the 261 with cancers elected not to have surgery. 17/160 (11%) had poorly differentiated grade For > 10 ng/ ml 40% organconfined Among : 216/686 (31%) By age: 50-59: 36/113 (32%) 60-69: 99/336 (29%) 73/216 (34%) Combined Abn or DRE PPV: a Legend for study biases and weaknesses: 1) not population-based or community setting; 2) selection (including self) and/or referral biases; 3) nonrandom study group accrual; 4) explicit inclusion/exclusion not ; 5) abnormal test not described; 6) incomplete application of appropriate reference (gold) standard (work-up bias); 7) lack of proper blinding in test interpretation; 8) failure to account completely for all subjects (including biopsy of all abnormal tests and reporting of clinical and pathologic stage data). For each study listed in this appendix, the presence of one or more of these deficiencies is denoted with the corresponding number (1-8). We chose not to qualify weight to the extent of each particular weakness. 264/1167 (23%) RP No other data a BPA = benign prostate hypertrophy; PC = prostate cancer; PL = pelvic lymph node dissection (metastasis); PPV = positive predictive value; RP = radical prostatectomy; RT = radiation therapy; No TX = No treatment. b ACS-NPCDP = American Cancer Society National Prostate Cancer Direction Project. The ACS-NPCDP used DRE abnormality (asymmetry, induration, or nodule) and/or TRUS abnormality (hypoechoic area greater than 5-7 mean not due to cyst, vascular structure, or artifact). Although 2,227 of 2,425 received during first examination (with DRE and TRUS), no patient was for alone. c 12 of 37 cancers had non suspicious DRE but 8 of the 12 had asymmetry or DRE that would have prompted biopsy elsewhere (Stamey). 14 of 16 cancers missed by TRUS had abnormal but benign findings (e.g., asymmetry) that would have been elsewhere. Routine systematic biopsy of > 4 not recommended. d This study 1940 purportedly asymptomatic men over a 4 1/2 year period and followed them with annual DRE, TRUS, and. exact number of men followed per year are, nor is it clear how many cancers were in each examination (apparent maximum of 3). It is also not clear whether all men received each test with each iteration. The data are presented in a confusing manner with multiple textual errors and miscalculations. is not a major determinant of biopsy and less that one-half of those with > 4 received biopsy. e DRE 33 of 57 cancers found (detection rate 33/2425 = 1.4%). TRUS 44 of 57 cancers found (detection rate 44/2425 = 1.8%). f The ACS-NPCDP continued to rely on DRE and/or TRUS abnormalities as the main determinants for recommending biopsy, although subsequent evaluations incorporated testing. For 144 of the 1972 men reported here data are unavailable. For clinical staging, this study uses a modification of Whitmore s classification: A1 defined here as TRUS-measured tumor volume < 0.2 cm3 (average diameter less than 0.7 cm). An unknown number of had biopsy within the study on the basis of > 10 ng/ml, although 11 of the 106 cancers resulted from this effort. Patients with > 10 ng/ml who had a negativeè set of systematic biopsies were re-evaluated with repeated TRUS and DRE in 12 months. It is not specified how many were re if these studies remained negative. Six other cancers were Èfound through non-protocol means (e.g., TURP in men who were not previously recommended for biopsy). Positive Predictive Value (PPV) of DRE was 22% ly and only 14% follow-up examination. The PPV for TRUS were 14% and 8%, respectively (combined DRE/TRUS PPV 37% and 32%). g study design and mode of data presentation is poor. Description of patient cohort and method of recruitment scant. Only with elevated who then had abnormal DRE were eligible for biopsy. Actual number who meet and then received biopsy were not reported. This study precludes fair comparison of DRE and, as only with elevated received DRE. Proper blinding was not specified. Their results have little usefulness and are not generalizable to an office-based screening population. h 68% compliance with biopsy performance for either/both DRE, abnormal. The cancer detection rates and positive predictive values reported in the paper ignore noncompliance and assume same proportion of positive biopsies would occur if all men meeting biopsy actually received systematic biopsies. Unfortunately, although 53% of study group reported symptoms of prostatism, the data for predictive values of each test and detection are not stratified by symptoms or race. PPV for abnormal DRE among those is 146/683 (21%). 86 Costs and Effectiveness of Prostate Cancer Screening in Elderly Men